©Whole Foods Magazine
December 1996

                                             Sports Nutrition: HMB

                             More than making Human Muscles Bigger:                        

                                  An interview with Dr. Steven L. Nissen


                                         Richard A. Passwater, Ph.D.


An ideal supplement improves your health while improving your appearance.  The early research on b-Hydroxy-b-Methylbutyrate (HMB) indicated that the HMB supplement lowers total and LDL cholesterol levels in blood and helps strengthen the immune system, while building muscles and burning body fat.  This news is certainly of interest to body builders and other athletes, but it may also become of interest to cancer, AIDS and muscular dystrophy patients.

From antiquity health has been associated with a Ahealthy looking@ body.  Eating and exercise habits that lead to Ahealthy looking@ bodies usually are the same habits that lead to good health.  It was the physical culturists such as Paul Bragg that had a lot to do with the beginning of the health food industry.  It was my early interest in learning why, after the mid-twenties, athletic performance declined with age -- even though the athlete trained just as hard and ate just as well -- that led me to study the aging process in 1959.  Today there is even a specialized field called sports nutrition that interests young people in nutrition and health, hopefully an interest that stays with them through life.

HMB has been available as a supplement targeted for building muscles and suppressing protein breakdown since October 1995, but until recently, the research studies were either animal studies or brief abstracts presented at scientific meetings.  Now detailed, full publications of the (human) clinical studies are available to allow independent scientific review.  These early clinical results are very exciting indeed, as are the anecdotal reports from users.

In addition to the research on HMB for building muscles, there are several decades of research behind HMB, arising primarily from its role in lowering cholesterol.  I had noted role of HMB in cholesterol synthesis in the early 1970s when it was known as 3-hydroxyisovaleric acid.  Although my main interest is in HMB as a health builder in that it builds the immune system and lowers cholesterol, most people are interested in its muscle-building and fat-burning actions. Accordingly, I have asked Dr. Steven Nissen to chat with us about his research on how HMB builds muscles.

Steven L. Nissen, D.V.M., Ph.D.  received his Doctorate of veterinary Medicine in 1976, his Masters of Science in 1977, and his Doctorate of Philosophy in 1981, all from Iowa State University.  Dr. Nissen has been a Postdoctoral research fellow and a NIH-Diabetes fellow at the Mayo Clinic in Rochester from 1979 to 1982.  He has been an Assistant Professor (1982-1987), Associate Professor (1987-1993), and since 1993, is a Professor in the Department of Animal Science at Iowa State University.  He is concurrently the CEO of Metabolic Technologies Inc.  Dr. Nissen has won the Outstanding Graduate Student Research Award at ISU in 1979, and the Walnut Grove Outstanding Research Award in 1992.  He has also been recognized in the scientific community for his research by receiving the National Institutes of Health Young Investigator Award in 1982.

My point in going into such detail with his biography is to make it clear that this is sound research over a considerable length of time by qualified investigators at an established university in this field.  You will also notice that the important discovery in biochemistry and nutrition has come from the field of animal sciences.  It wasn=t too long ago that virtually all of the discoveries came from this field.  The importance of good nutrition to milk production, wool production, meat production, etc. all reflect the health of the animal.  Farmers knew that good nutrition paid dividends in profit as well as health.  However, at the same time, established nutritionists in the field of human sciences generally refused to conduct studies with vitamins, minerals and other micronutrients essentially until the epidemiologist forced them to by their findings of the association of nutrients with decreased incidence of disease.  The field of nutrition owes a great debt to those pioneers in the animal sciences.   Now let=s get to the research findings.

Passwater:  Dr. Nissen, what brought your interest to muscle metabolism?

Nissen:  Most of my academic career relates to muscle and amino acid metabolism.  Specifically, I have been working on the amino acid leucine and how it=s metabolized in muscle and how it regulates muscle growth.  So it was a natural extension of this work that led us down the metabolic pathway to where we are today working with the leucine metabolite b-Hydroxy-b-Methylbutyrate or as it is more commonly referred to as HMB.

Initially, my interests in HMB were related to animal meat production.  Several early experiments focused on meat production in sheep, cattle and chickens.  Our interest in the human muscle metabolism and muscle strength really evolved out of a common interest between myself and Dr. Naji Abumrad, who at that time was at Vanderbilt University.  He essentially volunteered to do a Phase 1 study of the effect of HMB on protein metabolism.  From there a series of human studies evolved that created the safety and efficacy database we now have.

Dr. Abumrad and I have been colleagues in research for almost 15 years.  Two of our common links are our interest in leucine metabolism and isotopic modeling of protein metabolism.  In addition to his duties as Chief of Surgery at North Shore Medical Hospital, he is still involved in HMB research.

Passwater:  What led you to HMB C what was the eureka event or moment?

Nissen:  The experiment that crystallized the concept that HMB was the compound we should work on was an experiment that we actually conducted in isolated lymphocytes (small white blood cells critical to the immune system).  In this experiment we added every compound we could think of involved in the leucine metabolic pathway to isolate lymphocytes and measured growth.  The only thing that really showed an enhancement of lymphocyte function was HMB.  This really impacted our thinking and from then on we focused all our attention on HMB.

Passwater:  Why were you investigating the role of leucine metabolites on lymphocytes?

Nissen:  For some thirty years, this leucine pathway has been of interest in medicine and biochemistry.  This research really stemmed out of earlier research on the precursor to HMB or alpha-ketoisocoproate (KIC).  We found KIC was reasonably active in animals in simulating the immune system in stressful situations.  After considerable research on KIC, we finally asked the question, Aare there other compounds downstream in this metabolic pathway that may be responsible for this KIC effect?@  The answer to this was actually Ayes.@  HMB appears to be responsible for the effects of leucine and KIC on the lymphocytes.

Passwater:  Let=s talk about building muscles for a moment.  You have found that HMB works by protecting muscle cells from breaking down.  Many people have been taught that exercise builds muscles by first destroying the old muscle cells (catabolism) and they will be replaced by new and stronger muscle cells (anabolism).  Just what has to occur to build muscle and strength?  What is the relationship between catabolism and anabolism?

NissenMuscle cell growth is not a process of dying cells being replaced with new muscle cells.  We pretty much have the same number of muscle fibers that we are born with throughout life.  The process of building new muscle actually involves adding new nuclei and more protein within those fibers, or what we call hypertrophy.  Therefore, the process of building up muscle is the result of making new muscle protein and this, of course, is a fine balance between making protein (protein synthesis), and the normal process of tearing down proteins (proteolysis).  So, if we=re in a steady state of no growth, synthesis and breakdown are equally balanced.  During muscle growth (in response to stimuli such as weight lifting) protein synthesis is greater than protein breakdown.  What we and others have found is that intense muscle exercise actually increases both protein synthesis and protein breakdown.  We believe that what is unique about HMB is that it actually suppresses the breakdown portion of the balance with the net result being more muscle deposited.

Passwater:  HMB appears to affect white muscle fibers more than red muscles.  What is the significance of this?

Nissen:  We=re not quite sure if it is of significance.  The studies showing this effect in muscle were carried out in isolated rat muscles and basically we haven=t determined whether this translates to specific changes in humans that affect red versus white muscle.

Passwater:  What human studies have you conducted?

Nissen:  I have been involved in seven human studies relating to HMB.  These have been in both men and women, and in exercised and unexercised settings.  In addition, all the studies also had a safety/health component to them to collect data on the safety of HMB.  These studies are in various states of publication.  Many of the initial studies should be published by the beginning of 1997.

Passwater:  Have your studies indicated that along with the accelerated growth of lean tissue, there is a simultaneous reduction of body fat?

 Nissen:  In all the human studies the lean tissue growth response is accompanied by a reduction in body fat.  At this point, we don=t know whether there is a specific affect of HMB on body fat or whether it=s an indirect affect due to an increase in caloric utilization as a result of increased lean tissue burning up calories.

Passwater:  Have you tested HMB with any sports teams?

Nissen:  Yes, we have.  We have conducted a seven-week study with HMB on the Iowa State University Football Team during spring training which involved a great deal of aerobic and strength training.  Over the study, the HMB supplemented group responded with a 2 kilogram increase in fat-free mass (lean tissue gain) over and above the placebo group.  This study should be published in December in the Journal of Applied Physiology.

Passwater:  I have seen newspaper articles that mention that several U. S. Olympic athletes, especially swimmers, benefitted from HMB.

Nissen:  We don=t keep close tabs on this. but from what we hear, HMB is very popular with swimmers and some of the professional football teams.

Passwater:  Have there been studies with HMB in aerobic exercise?

Nissen:  Theoretically, HMB should spare energy in the muscle because it decreases protein turnover which is an energy consuming process.  Based on this theory and anecdotal reports of increased performance, I think this is worth a critical look.  There are studies currently underway looking at aerobic performance and results should be released by the end of this year.

Passwater:  In the human studies were blood cholesterol levels lowered?

Nissen:  Yes, in every study in humans there has been a drop in total cholesterol and LDL cholesterol.  Over all the human studies, this amounted to about a 7 - 8 percent decrease in LDL cholesterol.  HDL cholesterol levels in most studies tended to improve a little bit although statistically the numbers didn=t reach significant values.

Passwater:  It is obvious how HMB benefits  an athlete.  Will it benefit sedentary middle-aged individuals?

Nissen:  Although we do not yet have data collected in middle-aged individuals or the elderly, we have no reason to believe that the response would not be the same in all these groups if they were involved in an exercise program.  To date, the data would indicate that exercise is a necessary component to have maximal results while taking HMB.

Passwater: So couch potatoes will still have to do some exercise to get the body-building benefits of HMB.  Considering the amount of HMB needed for its known uses, cholesterol reduction, immune enhancement, fat reduction and body building, what can you tell us about its safety based on your human studies?

Nissen:  The fact that all of these benefits happen concurrently suggests an underlying common mechanism.  Relative to the safety of HMB, it is a normal product of body metabolism, it is found in the food we eat and appears to be an essential part of the tissue growth process.  In addition, it=s a water-soluble compound like water-soluble vitamins which are excreted in the urine in the proportion to the dietary intake.  Thus, based on the chemistry of HMB, it would be predicted that HMB is a relatively safe compound. 

In every human study that we=ve conducted there=s been an extensive safety profile conducted in terms of adverse effects and organ function.  In addition, we=ve given psychological profiles and physical exams in each study.  In none of these studies has there been an indication of a safety issue related to HMB.  The only changes in blood chemistry relate to a decrease in total and low-density lipoprotein (LDL) cholesterol levels.  Lastly, there have been animal studies and human studies in which high levels of HMB have been taken and there doesn=t appear to be any untoward effects.

Passwater:  Since HMB is found in both plants and animals, and it is produced in the human body, what advantages can be obtained by supplementation?

Nissen:  Our current working theory is that the body cannot make enough HMB in certain circumstances.  We think that HMB actually is an important source for cholesterol synthesis in muscle, the immune system, and the mammary gland.  This may sound strange, but these tissues must make cholesterol within the cell for use in cell functions such as building more muscle or immune cells and synthesis of fat in milk.

Passwater:  It certainly doesn=t sound strange to me.  That was one of my points in my 1972 publication in American Laboratory, ADietary cholesterol: Is it related to serum cholesterol or heart disease?@

Nissen:  ...Blood and dietary cholesterol are of little or no value in supplying cholesterol to these tissues.  Thus, in situations of high demand, such as immune cell activation, muscle growth, or milk production, there may be inadequate sources of cholesterol precursors in these tissues to support function.  Thus, our theory is that supplementing HMB provides a source for cholesterol synthesis that is essential for maximal organ function.

Passwater:  And this is at the same time that blood cholesterol levels are being reduced via the indirect result of muscle growth.  You mentioned the leucine C KIC C HMB metabolic pathway.  Where does the HMB that is produced in our bodies come from.  What are its precursors?  How much do we and other animals produce?

Nissen:  HMB is normally produced from the amino acid leucine.  Leucine can be derived from both protein in the diet or from the normal turnover of protein in the body.  It appears that muscle and liver are the major sites of HMB production although this hasn=t been extensively studied.  In humans we estimate that we make somewhere between 1/4 of a gram to one gram of HMB per day, depending on the protein intake.  If we take in extremely high levels of protein, it can be speculated that several grams of HMB could be made per day.

Passwater:  What levels of HMB are found in foods?

Nissen:  We found that most foods have HMB concentrations from 1-10 micromoles  per kilogram range of HMB.  However, in some plant products such as alfalfa, some fermentation products, and some meats such as catfish, concentrations can reach greater than 20 times higher than most foods.  Nonetheless, foods are not a significant source of HMB under normal circumstances.

Passwater:  How much HMB do you recommend as a supplement for body-building?  Is there a maintenance dosage that is lower than a loading dosage?  Should HMB be taken with meals?

Nissen:  It appears that three grams of HMB is optimal for the athlete undergoing an intensive exercise program.  Other dosages of HMB related to either loading or maintenance are really unclear at this point.  Studies have been done at higher levels but there doesn=t appear to be any added advantage.  As far as when it should be taken, we recommend it be taken with meals primarily so that it is available concurrent with meal absorption.

Passwater:  You said that three grams is optimal for the serious body-builder.  My experience with body-builders and other athletes is that they often feel that they will get faster and better results if they go above the recommended levels.

Nissen:  We really feel that based on our animal research and all of our human studies that higher doses of HMB will really not result in any faster or bigger gains.

Passwater:  How do the results obtained with HMB compare to those alleged with harmful steroids?

Passwater:  We really don=t know how HMB compares with steroids in terms of its effects.  It is my understanding that steroids affect primarily the protein synthetic arm of protein metabolism whereas HMB appears to slow the protein breakdown arm of protein metabolism.  Given this and the fact that HMB is water-soluble, we believe that HMB should be classified as a nutrient whereas steroids would be in a different classification.

Passwater:  Do members of your research team take HMB?

Nissen:  Most of them do.  The problem that we have is finding time to do the required exercise but when we do find the time to exercise, the results are very good.

Passwater:  I think we are all subject to the time problem -- research, writing, traveling, lecturing C little time left for taking care of ourselves.  Maybe HMB will be the impetus for many of us to get back to proper exercising.  Are you studying the health benefits of HMB in the wasting diseases such as cancer, AIDS, amyotrophic lateral sclerosis (ALS), muscular dystrophy and other dystrophies?

Nissen:  Yes, we have studies underway right now in AIDS patients.  This is a study looking at both immune function and wasting in subjects with AIDS.  Studies are in the planning stages to look at dystrophies, especially muscular dystrophy.

Passwater:  Is there a secondary pathway for HMB production that occurs in disease states or other abnormal states?

Nissen:  In diabetes, starvation, and inborn errors of leucine metabolism, blood leucine levels are extremely high, and because of these high levels, high rates of HMB production can be achieved.  This doesn=t necessarily relate to physiology, but instead HMB is a byproduct of high levels of blood leucine.

Passwater:  What is the relationship between HMB and biotin?

Nissen:  In certain circumstances of severe biotin deficiency, leucine metabolism cannot proceed normally, which results in increased HMB levels in blood and urine.  Thus, blood levels of HMB have been used as an indicator of biotin status in both animals and humans.  This really has very little consequence relative to normal HMB metabolism.

Passwater:  How does HMB improve the immune system?

Nissen:  In an activated immune system such as occurs with an infection, the cells differentiate and divide.  To do this, they must obtain a source of cholesterol because cholesterol is an essential component of the cell, especially the cell membrane.  What we=re theorizing is that HMB provides a precursor source for cholesterol synthesis allowing the cells to maximally perform in an activated situation.

Passwater:  Is HMB involved in regulation of homeostasis?

Nissen:  I don=t think that HMB is really involved in homeostasis any more than a vitamin is.  HMB is simply supplying a biochemical to cells that is necessary in normal function.  Dietary supplementation is only effective when endogenous sources are inadequate.

Passwater:  Such as during the building of muscles.  According to your studies, HMB seems to be important to producing better feed-to-meat conversion in animals.  Is HMB cost-effective for this purpose?

Nissen:  At the present time, HMB is not cost-effective for farm animals.  We see this changing over the long run and do expect to have HMB in animal feed in 18-24 months.

Passwater:  In which mammalian systems has HMB been studied?

Nissen:  HMB has been studied in cattle, sheep, pigs, chickens, horses, rabbits, guinea pigs, rats, goats and quail.  HMB has been fed to about 10,000 animals.

Passwater:  You have also studied body composition in farm animals.  Does HMB improve specific areas better than others and is it important in other areas of livestock production?

Nissen:  We think the major application for HMB right now in animals is related to health.  We=ve conducted studies in thousands of animals and a very consistent and reproducible affect is that HMB supplementation improves animal health.  This is reflected in both mortality of animals and in the morbidity of animals.

Passwater:  You did several studies on physical stress such as confinement and shipping and handling.  What effect does this type of stress have on the body and why did HMB help?

Nissen:  Again, this goes back to what we believe HMB is doing in the body, and that is basically allowing maximal activation of the immune system in the body.  During handling, immune function actually goes down because of increases in the hormone cortisol.  HMB basically gives the animal the ability to maintain a more normal immune system and fight infections in a more appropriate manner.

Passwater:  Where does your research take you from here?

Nissen:  The focus of HMB research is really going to be a two-pronged attack.  One is a basic emphasis trying to figure out if indeed our theory of HMB action through cholesterol synthesis is correct.  The other emphasis relates to the clinical aspects of HMB in humans, especially related to the effects on aerobic training, immune compromised individuals, and the elderly.


© 1996 Whole Foods Magazine and Richard A. Passwater, Ph.D. This article is copyrighted and may not be re-produced in any form (including electronic) without the written permission of the copyright owners.